This RFA intends to establish clinical sites, as part of an undiagnosed diseases network (UDN), to provide further evaluation for patients that have been through the diagnostic odyssey with no diagnosis found. The research team at Duke is robustly positioned to establish such a clinical site. Building on the strong collaboration between the two principal investigators, a successful genome sequencing clinic has been established for patients with unidentified genetic disorders. Utilizing careful clinical screening, detailed phenotyping, exclusion of contributing environmental factors and copy number variants; whole exome sequencing has been performed and causal variants have been identified in approximately 50% of patients. The causal variants have been communicated to the patients/families with genetic counseling and further medical care for the patients has been arranged. In addition to experience with genome sequencing, we also have experts in rare disorders as part of the investigative team and the infrastructure essential to evaluate patients referred through the UDN. This includes a multidisciplinary team of world-class clinicians consisting of both pediatric and adult specialists who will be performing in-depth clinical evaluations of the patients and will take part in research- related discussions regarding clinical correlation of genetic sequence data, data analysis and final conclusions and the Duke Clinical Research Unit (DCRU) that has the capability to house medically-critical patients and provides a clinical atmosphere for all necessary specialist evaluations. Our aims are: Specific Aim 1: Comprehensively evaluate patients with undiagnosed diseases, capitalizing on our center's range of diagnostic specialties and select patients eligible for genome sequencing. Specific Aim 2: Analyze genome sequence data to identify causal variants and other variants of interest to the phenotypes, utilizing our experience in mutation identification in rare, isolated genetic disorders. Specific Aim 3: Effectively communicate results and provide genetic counseling to the patients and their families, drawing upon the experience we have gained thus far. Specific Aim 4: Assess the patients' expectations and understanding of the results of the diagnostic genome sequencing and assist in the development of common protocols to assess this across the UDN. An innovative aspect of our proposal is the assessments of patients and families' perceptions about the process and outcomes. This practice would be particularly useful to help develop protocols for common practices within the UDN. With the experience the research and clinical team has accrued and the framework proposed, we are strongly positioned to be a clinical site for rare and undiagnosed diseases, with the ability to evaluate patients across the life-span.